Rickettsioses are infections caused by Rickettsiae in which animals
are the hosts and arthropods are the vectors. Rickettsiae are named
after Dr. Howard Ricketts (1871-1910), who was the scientist that first
identified them and described the transmission of one rickettsial
species via its tick vector. Rickettsiae are bacteria with atypical
morphology, physiology, and behavior. In general they are small,
gram-negative, pleomorphic (cocci or small bacilli) bacteria that are
obligate intracellular parasites of eukaryotic cells. Some species that
originally were classified in the Rickettsiaceae family have been
reassigned to different families. Rickettsia, Orientia, Ehrlichia,
Anaplasma, and Neorickettsia are all small obligate intracellular
bacteria which were once thought to be part of the same family; however,
they are currently considered to be distinct unrelated bacteria. There
are several genera in the Rickettsiaceae family including Rickettsia and
Orientia and several genera in the Anaplasmataceae family including
Anaplasma, Neorickettsia, and Ehrlichia. Typically these bacteria are
not transmissible directly from person to person (other than by blood
transfusion or organ transplantation); transmission typically occurs via
an infected arthropod vector or through exposure to an infected animal
reservoir host.

All rickettsioses are zoonoses with the exceptions of epidemic
typhus and trench fever in which humans are the hosts and lice are the
vectors. Rickettsioses may cause relatively mild disease
(rickettsialpox, cat scratch disease, and African tick-bite fever) or
they may cause severe disease (epidemic typhus, RMSF, and Oroya fever).
They can also vary in duration from those that are self-limiting to
chronic or those that recur.

Causative Agent

Rickettsiaceae are small bacteria in the family Rickettsiaceae and
are fastidious, nonmotile, aerobic, gram-negative, obligate
intracellular bacteria that survive only briefly outside the host. They
multiply by binary fission intracellularly in host cells. Rickettsiae
are among the smallest cells, ranging in size from 0.3 to 0.6 [micro]m
wide and from 0.8 to 2.0 [micro]m long. The nutritional requirements of
Rickettsiae are based on the host cell because of their inability to
metabolize a precursor to the energy producing molecule ATP (adenosine
triphosphate). Most Rickettsiae have life cycles that depend on an
exchange between blood-sucking arthropod and vertebrate host. Humans are
often accidental (dead end) hosts. The mechanism by which Rickettsiae
cause disease is not clearly understood; however, most infections target
the endothelial lining of small blood vessels.

For years Rickettsiae were believed to be
related to viruses because they are very
small and can only multiply in living
host cells.

Epizootiology and Public Health Significance

Table 4-3 summarizes the distribution of rickettsiosis, which
varies with the disease.

The taxonomy of this group of
organisms has recently changed and will
likely change again.

Rickettsial zoonoses may occur sporadically or endemically. Rarely
do they occur in epidemics (such as Q fever as a result of its aerosol
transmission). The incidence of rickettsial disease varies, but in
general is uncommon in humans (but when they occur can cause serious
disease).

Transmission

Rickettsioses are transmitted by arthropod vectors that vary with
the disease. These arthropod vectors feed on the blood or tissue fluid
of the vertebrate host. The rickettsial bacterium is transmitted in a
variety of ways including through direct inoculation with arthropod
saliva, direct inoculation into the skin lesion as they feed, release of
the rickettsiae onto the skin or into a wound via the smashing of the
vector or the arthropod defecating into the area, or other means (such
as fomites, animal products, and food).

Pathogenesis

A common target in most rickettsioses is the endothelial lining of
small blood vessels such as venules and capillaries. Rickettsiae
recognize, enter, and multiply in endothelial cells causing necrosis. In
an effort to repair the necrotic endothelium, the host responds by
proliferating endothelial cells that eventually block the vascular lumen
(center of the blood vessel). Pathologic changes such as vasculitis,
perivascular infiltration by inflammatory cells, increased vascular
permeability resulting in fluid leakage, and thrombosis are common
conditions seen with rickettsioses. Specific organ involvement would
depend on the blood vessels affected. For example, intravascular
clotting of blood cells in vessels supplying blood to the brain results
in changes in mentation and other neurologic signs that may occur with
some diseases. Target organs of rickettsial diseases include skin, lung
tissue, heart, brain, gastrointestinal tract, pancreas, liver,
coagulation system, and kidney.

Clinical Signs in Animals

Typically there are not clinical signs of rickettsial infection in
animals and animals serve as reservoir hosts of the bacterium.

Clinical Signs in Humans

Clinical signs of rickettsial illnesses vary in humans, but typical
early nonspecific signs include fever, headache, and lethargy. Rashes
and eschars (black scabs) may be associated with some rickettsioses.

Diagnosis in Animals

Diagnosis of rickettsioses is typically not done in animals.

Diagnosis in Humans

Rickettsioses are diagnosed based on clinical signs, history of
arthropod exposure, development of specific acute and convalescent
antibody levels reactive for a specific pathogen or antigenic group, a
positive result for a serologic test method, such as PCR, IFA, or ELISA
test, or isolation of the rickettsial bacterium.

Treatment in Animals

Animals are not routinely treated for rickettsioses.

Treatment in Humans

Treatment of rickettsioses is similar and includes antibiotics
(most often doxycycline, tetracycline, or chloramphenicol) and
supportive care (antipyretics, analgesics, and fluid therapy). Treatment
is initiated based on clinical signs and arthropod exposure prior to
obtaining test results.

Management and Control in Animals

The best way to prevent domestic animals from contracting
rickettsioses is to limit their exposure to arthropods, particularly
ticks. Inspection for ticks and tick removal and the use of topical
agents or tick collars are effective methods of tick control. Vaccines
that protect against rickettsiosis in the United States are not
available (other than Neorickettsia risticii, the agent of equine
monocytic ehrlichiosis, more commonly known as Potomac horse fever).

Management and Control in Humans

The best way to prevent humans from contracting rickettsioses is to
limit their exposure to arthropods as previously described. There are no
commercially licensed vaccines for rickettsioses available in the United
States. Vaccinations to prevent rickettsial infections are not required
by any country as a condition for entry.

Summary

Rickettsioses are infections caused by Rickettsiae in which animals
are the hosts and arthropods are the vectors. Rickettsiae are bacteria
with atypical morphology, physiology, and behavior and are typically
small, gram-negative, pleomorphic bacteria that are obligate
intracellular parasites of eukaryotic cells. There are two families of
bacteria that cause rickettsioses: Rickettsiaceae (Rickettsia and
Orientia) and Anaplasmataceae (Anaplasma, Neorickettsia, and Ehrlichia).
Typically these bacteria are transmitted via an infected arthropod
vector or through exposure to an infected animal reservoir host.

All rickettsioses are zoonoses with the exceptions of epidemic
typhus and trench fever in which humans are the hosts and lice are the
vectors. Rickettsioses may range from those that cause relatively mild
disease to those that cause severe disease. Typically there are not
clinical signs of rickettsial infection in animals and animals serve as
reservoir hosts of the bacterium. Clinical signs of rickettsial
illnesses vary in humans, but typical early nonspecific signs include
fever, headache, and lethargy. Rashes and eschars may be associated with
some rickettsioses.

Rickettsioses are diagnosed based on clinical signs, history of
arthropod exposure, development of specific acute and convalescent
antibody levels reactive for a specific pathogen or antigenic group, a
positive result for a serologic test method such as IFA or ELISA
testing, isolation of the rickettsial bacterium, or PCR testing.
Treatment of rickettsiosis includes antibiotics and supportive care. The
best way to prevent domestic animals and humans from contracting
rickettsioses is to limit their exposure to arthropods--particularly
ticks.

EHRLICHIOSIS/ANAPLASMOSIS

Overview

Ehrlichioses and Anaplasmoses are tick-borne diseases caused by
small, intracellular bacteria belonging to the Rickettsiaceae family and
originally belonging to the Ehrlichia genus. Ehrlichiosis was first
described in Algerian (Africa) dogs in 1935 (caused by Ehr. canis). The
next outbreak of canine ehrlichiosis was in military guard dogs
stationed in Vietnam during the 1960s in which a large number of dogs
became ill and died because of hemorrhagic complications of the disease.
Ehrlichiosis in humans was first described in 1954 in Japan and was
called Sennetsu fever. Sennetsu fever, caused by Ehr. sennetsu, occurs
in limited areas of the Far East (primarily Japan) and is extremely
rare. Sennetsu fever was the only form of ehrlichiosis known to afflict
humans for many years until 1986 when a Detroit man became sick after
being exposed to ticks in rural Arkansas. From that time on, cases of
human ehrlichiosis have been diagnosed in the United States annually
primarily in the southeastern and southcentral states. Originally human
cases of ehrlichiosis were attributed to Ehr. canis, but in 1990, the
CDC isolated a new species of Ehrlichia from the blood of a U.S. Army
reservist training at Fort Chaffee, Arkansas. This new species of
Ehrlichia was named Ehr. chaffeensis. In 1956, American C. B. Philip
gave the name Ehrlichieae to this family of bacteria, after Paul
Ehrlich, who initially described a disease associated with small,
gram-negative bacteria known to infect cattle, sheep, goats, and dogs.
Ehr. ewingii was named in 1992 after Sidney Ewing, a veterinary
pathologist and investigator of ehrlichioses, who found the organism in
neutrophils of a febrile dog.

In 2001, the taxonomy of this group changed with some species of
Ehrlichia being reclassified into the genera Anaplasma or Neorickettsia.
All of these organisms were placed in the Anaplasmataceae family.
Anaplasma phagocytophilum now contains the bacteria known as Ehr. equi
and Ehr. phagocytophila.

Ehrlichiosis is a term historically used to describe three
tick-borne diseases caused by intracellular bacteria of the genus
Ehrlichia. Ehrlichiosis was originally named according to the host
species and type of white blood cell most often infected. Human
monocytic ehrlichiosis (HME) was described in 1986 and is caused by Ehr.
chaffeensis; human granulocytic anaplasmosis (HGA), which was formerly
known as human granulocytic ehrlichiosis (HGE) was described in 1993 and
is caused by Ana. phagocytophilum (formerly Ehr. phagocytophilis); and
Ehr. ewingii ehrlichiosis caused by Ehr. ewingii was first described in
St. Louis, MO, in 1999. Canine monocytic ehrlichiosis is caused by Ehr.
canis and occasionally Ehr. chaffeensis; canine granulocytic
ehrlichiosis is caused by Ana. phagocytophilum (formerly Ehr.
phagocytophilis) and Ehr. ewingii; equine granulocytic ehrlichiosis is
caused by Ana. phagocytophilum; and equine monocytic
ehrlichiosis/Potomac horse fever is caused by Neorickettsia risticii
(formerly Ehr. risticii). Zoonotic species include Ehr. chaffeensis,
Ehr. ewingii, Ana. phagocytophilum, and Neorickettsia sennetsu (Ehr.
canis may also be zoonotic, but this is not confirmed).

Causative Agent

The family Anaplasmataceae now contains four genera: Ehrlichia,
Anaplasma, Neorickettsia, and Wolbachia (found only in arthropods). The
zoonotic species of this group of organisms include Ehr. chaffeensis,
Ehr. ewingii, Ana. phagocytophilum, and N. sennetsu. Ehr. canis may be
zoonotic. The organisms currently believed not to be zoonotic are Ehr.
bovis (causes bovine petechial fever in cattle in the Middle East and
Africa), Ehr. muris (found in rodents in Japan and does not cause
disease), Ehr. ondiri (found in cattle and wild ruminants in Africa),
Ehr. ovina (found in sheep in the Middle East), Ehr. ruminantium (causes
heartwater disease in ruminants), Ana. platys (causes cyclic canine
thrombocytopenia in the United States, Taiwan, Greece, and Israel), and
N. risticii (causes Potomac horse fever/equine monocytic ehrlichiosis in
the United States). The bacteria in this group of organisms are small,
pleomorphic, nonmotile, gram-negative, obligate, intracellular bacilli
(they parasitize leukocytes). These bacteria survive only briefly
outside the host (reservoir or vector) and only multiply intracellularly
(Figure 4-18).

Ana. phagocytophilum contains the
organism formerly known as
Ehr. equi and Ehr. phagocytophila.

Within a cell, small elementary bodies develop into larger initial
bodies and eventually into intracytoplasmic inclusion bodies called
morulae (which are diagnostic in blood smears). These organisms do not
grow well on routine culture media and are typically cultured in
embryonated eggs and in tissue culture.

[FIGURE 4-18 OMITTED]

Epizootiology and Public Health Significance

Ehr. chaffeensis, Ehr. canis, and Ana. phagocytophilum have
worldwide distribution. In the United States, Ehr. chaffeensis occurs in
more than 30 states (particularly Missouri, Tennessee, Oklahoma, Texas,
Arkansas, Virginia, and Georgia). In the United States Ana.
phagocytophilum is endemic is Wisconsin, Minnesota, Connecticut, and
Massachusetts. Ehr. ewingii has only been found in the southeastern and
southcentral United States. N. sennetsu has been reported mainly in
Japan, but is probably found in other parts of Asia as well. In some
cases, particular diseases are not reported from the bacterium's
entire geographic range (for example Ana. phagocytophilum is found
worldwide, but only causes tick-borne fever in ruminants in Europe,
India, and South Africa).

Approximately 1,200 cases of ehrlichiosis/anaplasmosis were
reported in the United States from 1986 to 1997. Human monocytic
ehrlichiosis is most commonly seen in the Southeast and Midwest United
States; human granulocytic anaplasmosis is most commonly seen in the
Northeast and upper Midwest United States. Most cases of ehrlichiosis
occur from April to September. Approximately half of all people with
human monocytic ehrlichiosis require hospitalization.

About 2% to 3% of human monocytic ehrlichiosis cases, 7% of human
granulocytic anaplasmosis cases, and 5% to 10% of Ehr. chaffeensis
infections are fatal. Infection with Ehr. ewingii is rare and most
people recover without complications. Sennetsu fever is usually a mild
illness and is not a significant cause of disease in the United States.

Transmission

Ehrlichiosis is a tick-borne disease and is transmitted by ticks in
the family Ixodidae.

The following bacteria are transmitted by the following hard ticks
(Figure 4-19):

* Ehr. chaffeensis is transmitted mainly by Amblyomma americanum
(Lone Star tick), but has also been seen in De. variabilis (American dog
tick).

* Ana. phagocytophila is transmitted by I. scapularis (the
black-legged tick) in the eastern United States, I. pacificus (western
United States), and I. ricinus (Europe).

* N. sennetsu has an unknown vector but may be transmitted by
consumption of raw fish infested with helminths or by a tick.

Transovarial transmission is not believed
to occur with members of the Ehrlichia
genus; ticks appear to become infected
as larvae or nymphs.

[FIGURE 4-19 OMITTED]

Most cases of ehrlichiosis/anaplasmosis are acquired during the
months of highest tick activity, which is typically April to October
with maximum activity occurring in June and July.

Transmission can also occur by blood transfusion. Viable bacteria
have been found in refrigerated samples at 4[degrees]C for up to a week.

Pathogenesis

Bacteria that cause ehrlichiosis/anaplasmosis bind to the cell
surface of leukocytes (a different leukocyte is preferred by different
bacteria) and invade and live in these cells ultimately altering the
immune system of the infected animal/person, thereby lessening the
body's ability to fight secondary infections. These bacteria live
and reproduce in the cytoplasm and are most frequently found clustered
together as aggregates of many organisms. These clusters are berry-like
in appearance and are called morulae. Little is known about how the
infection spreads from the initial tick bite site, what cells or tissues
are involved, what causes illness, and how tissue damage occurs.

The ticks that transmit Bo. burgdorferi
and Bab. microti also transmit
ehrlichiosis.

Clinical Signs in Animals

Ehrlichia infections have been reportable
to the CDC since 1998.

The variety of different bacteria in this group can cause a variety
of clinical signs in a variety of animals. Ehr. chaffeensis can infect
dogs, coyotes, red foxes, deer, goats, and lemurs (causing disease in
dogs and lemurs). The reservoir hosts for Ehr. chaffeensis are deer.
Ehr. ewingii causes disease in dogs. Dogs may also be the reservoir
host. Ehr. canis infects dogs, wolves, and jackals; these animals are
also the reservoir hosts. Ana. phagocytophilum causes disease in dogs,
horses, llamas, cats, cattle, sheep, goats, and nonhuman primates.
Reservoir hosts are deer, elk, and rodents.

Diseases in animals caused by bacteria in this group include:

* Canine monocytic ehrlichiosis. Most cases of canine monocytic
ehrlichiosis are caused by Ehr. canis (however, Ehr. chaffeensis
infections are possible and are clinically indistinguishable from Ehr.
canis) and are reported throughout the year (the tick vector can survive
indoors and the disease course is prolonged in dogs). There are three
stages of this disease: acute, subclinical, and chronic, which are
difficult to differentiate in naturally-infected dogs.

* Acute disease typically lasts for one to four weeks and can
display a wide variety of clinical signs ranging from mild to severe
with nonspecific signs such as fever, lethargy, anorexia,
lymphadenopathy, splenomegaly, and weight loss. Bleeding disorders such
as anemia and petechial hemorrhages may be seen. Ocular lesions such as
anterior uveitis, oculonasal discharge, corneal opacity, and subretinal
hemorrhages may occur. Other signs that may be seen include vomiting,
diarrhea, lameness, neurologic signs (ataxia, seizures, and vestibular
dysfunction), coughing, and dyspnea.

* Subclinical disease occurs when dogs recover from the acute phase
and remain infected for months or years. Dogs with subclinical disease
can remain infected without showing clinical signs, may clear the
infection, or may progress to the chronic phase.

* Canine granulocytic anaplasmosis (formerly canine granulocytic
ehrlichiosis). This disease is caused by the organisms Ana.
phagocytophilum and Ehr. ewingii and resembles monocytic ehrlichiosis.
The most commonly seen sign with canine granulocytic ehrlichiosis is
polyarthritis (it is uncommon with monocytic ehrlichiosis). Moderate to
severe anemia has also been seen with this disease process.

* Equine granulocytic ehrlichiosis. Equine granulocytic
ehrlichiosis is caused by the organism Ana. phagocytophilum and the
disease varies from a mild infection with fever to severe disease.
Clinical signs are more severe in older animals and include fever,
anorexia, ataxia, jaundice, petechial hemorrhages, and peripheral edema
(mainly hind limb). Equine granulocytic ehrlichiosis is most commonly
seen in California, with sporadic cases occurring in other states. Most
cases are seen in late fall, winter, and spring. Illness is more severe
in older horses and animals are immune for at least two years following
recovery.

* Equine monocytic ehrlichiosis (Potomac horse fever). Equine
monocytic ehrlichiosis is caused by N. risticii and is a serious illness
of horses first described in the area around the Potomac River in
Maryland in 1979 (it is now recognized throughout the United States and
other countries). After the organism is ingested, it multiplies in the
intestinal tract, where it can cause marked inflammation. Clinical signs
include fever, depression, poor appetite, and diarrhea. Some horses will
develop laminitis and pregnant mares can abort.

* Tick-borne fever. Tick-borne fever is seen in domestic and wild
ruminants especially sheep and cattle and is caused by the organism Ana.
phagocytophilum.

Most ruminants will recover from this disease within 2 weeks, but
relapses may occur. Tick-borne fever usually occurs in the spring and
early summer when dairy cattle are turned out onto pasture. Impaired
immunity seen with this disease will make the animals more susceptible
to concurrent infections with some infections persisting for up to 2
years following clinical recovery. After one or two bouts of tick-borne
fever sheep and cattle can develop immunity that can last for several
months, but will decrease rapidly once the animal is removed from an
endemic region. Death is rare.

* Sheep. Tick-borne fever in sheep is mainly seen in young lambs
born in tick-infested areas and in newly introduced older sheep. The
main clinical sign is sudden fever that lasts for 4 to 10 days; other
signs include weight loss, lethargy, coughing, tachypnea, and
tachycardia. Pregnant ewes introduced onto infected pastures during the
last stages of pregnancy can abort. Abortion is usually seen 2 to 8 days
after fever onset. Infected rams may develop reduced sperm quality.

* Cattle. Tick-borne fever is usually seen in dairy cattle turned
out onto pasture with animals displaying a variety of clinical signs and
severity of signs. Anorexia, decreased milk production, dyspnea,
coughing, abortions, and reduced semen quality can be seen with
tick-borne fever; abortions resulting in reduced milk yield and
respiratory disease are the most common clinical findings in cattle.

* Sennetsu fever. Dogs have been experimentally infected with N.
sennetsu developing fever as the only clinical sign. Mice have been
experimentally infected with the same organism causing diarrhea,
weakness, lymphadenopathy, and death.

* Ehrlichiosis in cats. Documented cases of ehrlichiosis in cats
are rare. Cats infected with Ana. phagocytophilum have had clinical
signs of fever, anorexia, lethargy, dehydration, and tachycardia.

Human infections with Anaplasmataceae organisms have been reported
since the 1950s (N. sennetsu); however, most cases of infection were
found in the 1980s (Ehr. chaffeensis, Ehr. ewingii, and Ana.
phagocytopyhilum). Ehr. canis has been isolated from only one
asymptomatic person.

* Ehrlichiosis in humans consists of the clinically similar
diseases human monocytic ehrlichiosis (HME) (Figure 4-20), which affects
monocytic cells and is caused by Ehr. chaffeensis; human granulocytic
anaplasmosis (HGA) (Figure 4-21), which affects neutrophils and is
caused by Ana. phagocytophilum; and Ehr. ewingii ehrlichiosis caused by
Ehr. ewingii. Human disease caused by Ehr. ewingii has only been
reported in a few immunocompromised patients. Ehrlichiosis in people
resembles RMSF (with or without the rash) with clinical signs beginning
approximately 7 to 10 days after infection. The rash occurs in 20% to
40% of cases particularly in children and tends to be spotted in nature
and is less prominent than that seen in RMSF. The rash can involve the
trunk, legs, arms, and face, but usually spares the hands and feet. In
people, symptoms vary greatly in severity, ranging from mild infection
where no medical attention is needed, to a severe, life-threatening
condition. Early symptoms are nonspecific and include high fever,
headache, chills, and muscle pain (which mimics the early symptoms of
many other tick-borne diseases). Other signs include vomiting, diarrhea,
abdominal pain, anorexia, photophobia, conjunctivitis, joint pain,
coughing, and mental confusion. Severe symptoms are seen in
immunocompromised people and include fever, renal failure, opportunistic
infections, hemorrhages, multisystem organ failure, cardiomegaly,
seizures, and coma. Complications are more commonly seen in human
granulocytic anaplasmosis.

* Sennetsu fever (caused by N. sennetsu) in people is a mild
infection resembling mononucleosis. Clinical signs include fever,
lethargy, anorexia, lymphadenopathy, hepatosplenomegaly, chills,
headache, and backache. Circulating mononuclear cells and atypical
lymphocytes are often increased. People with Sennetsu fever rarely have
a rash and deaths from this disease have not been reported.

* Ehr. canis may be rarely zoonotic and its zoonotic potential
needs to be confirmed.

[FIGURE 4-20 OMITTED]

[FIGURE 4-21 OMITTED]

Diagnosis in Animals

Ehrlichiosis/anaplasmosis in animals can be suspected based on
clinical signs and gross pathology. Dogs with canine ehrlichiosis
develop nonspecific gross lesions that include splenomegaly,
lymphadenopathy, and congested, discolored lungs. Animals may be
emaciated, have pale mucous membranes, and hemorrhages of the
gastrointestinal tract, heart, urinary bladder, lungs, and eyes. Lymph
nodes may be enlarged and discolored. Ascites and edema of the legs may
also be seen. Horses with equine granulocytic ehrlichiosis may have
petechial hemorrhages, subcutaneous edema, edema of the legs, and
interstitial pneumonia. Sheep and cattle with tick-borne fever may
abort. Complete blood count (CBC) abnormalities include thrombocytopenia
(most common), anemia, and leukopenia. Diagnosis can also be supported
by a response to treatment.

Unlike Rickettsiae, Ehrlichiae do
not cause vasculitis, but cause
multisystem diseases and can be found
in many organs by lymphohistolytic
(lymphocytes and macrophages)
infiltrates (such as gastrointestinal,
kidney, hearts, bone marrow, liver,
spleen, meninges, and CNS).

Laboratory tests for ehrlichiosis include serology or detection of
the organism. Co-infection and cross-reactions may make diagnosis of
this disease difficult. Bacterial culture is not used because these
organisms can be difficult to culture and can take up to 30 days to
grow. Detection of the organism is done by finding morulae in peripheral
blood smears or impression smears from fresh tissues stained with Giemsa
or by immunofluorescence. The morulae are typically seen in monocytes or
granulocytes. Detection of organisms is more useful in cases of equine
granulocytic ehrlichiosis than in cases of canine ehrlichiosis.
Serologic tests include indirect immunofluroescent antibody tests
(equine granulocytic ehrlichiosis, canine ehrlichiosis/anaplasmosis, and
tick-borne fever), ELISA tests (canine monocytic ehrlichiosis and canine
granulocytic anaplasmosis), and immunoblotting techniques such as
Western blotting (research use). Disease is usually confirmed by the
presence of rising antibody titers; in dogs, a single positive titer is
evidence of exposure. PCR assays that detect antigens in blood are
available for equine ehrlichiosis and may become available for canine
ehrlichiosis/anaplasmosis.

Diagnosis in Humans

Diagnosis in people is based on history, clinical signs, and
abnormalities on blood work (CBC and serum chemistry panels). Bacterial
culture is difficult and time-consuming (Ana. phagocytophilum and Ehr.
chaffeensis have been isolated from the blood of acutely ill people
using various cell lines). Detection of the organism can be done by
finding morulae in neutrophils or mononuclear cells. Disease
confirmation is done through serologic testing which consists of
indirect immunofluorescence assay (human monocytic ehrlichiosis or human
granulocytic anaplasmosis and Sennetsu fever). The current case
definition by the CDC for human ehrlichiosis/anaplasmosis is a fourfold
rise or fall in antibody titer. ELISA tests are being developed for
ehrlichiosis. PCR testing is available; immunohistochemistry and in situ
hybridization has been done on tissue samples such as the spleen and
lymph nodes.

Treatment in Animals

Ehrlichiosis/anaplasmosis is treated with tetracycline antibiotics.
Early treatment of equine granulocytic ehrlichiosis and tick-borne fever
are usually effective. Early treatment is critical for canine
ehrlichiosis and uncomplicated cases respond well. Treatment of the
chronic severe form in dogs is difficult and may require combination
therapies (glucocorticoids, chemotherapy drugs such as vincristine, and
hematopoietic growth factors).

Treatment in Humans

Treatment of ehrlichiosis/anaplasmosis in humans involves the use
of tetracycline antibiotics; the current drug of choice is doxycycline.
Early treatment is critical and prolonged treatment may be needed for
severe or complicated cases.

Management and Control in Animals

The best way to prevent dogs from contracting ehrlichiosis is to
limit their tick exposure. Dogs should be inspected daily for ticks and
any ticks that are found should be removed quickly and safely with a
gloved hand. Topical agents (such as fiprinol or permethrin) and tick
collars containing amitraz are effective methods of tick control.

Vaccines are not available for canine ehrlichiosis, equine
granulocytic ehrlichiosis, or tick-borne fever. There is a vaccine for
equine monocytic ehrlichiosis (Potomac horse fever). Prophylactic
antibiotics are sometimes used to prevent tick-borne fever in ruminants.

Management and Control in Humans

The best way to prevent ehrlichiosis or anaplasmosis in people also
includes tick control. Strategies to reduce ticks include area-wide
application of acaricides (chemicals that will kill ticks and mites),
application of tick repellent with DEET, and control of tick habitats.
Prompt removal of ticks is also essential. Tick control has been covered
in the tick biology section and should be referred to. There is no
vaccine for ehrlichiosis.

Summary

Ehrlichiosis and anaplasmosis are tick-borne diseases that are
transmitted by ticks in the family Ixodidae. The various types of
ehrlichioses/anaplasmosis are named according to their host species and
white blood cell type infected. Human monocytic ehrlichiosis is caused
by Ehr. chaffeensis; human granulocytic anaplasmosis is caused by Ana.
phagocytophilum; and Ehr. ewingii ehrlichiosis is caused by Ehr.
ewingii. Canine monocytic ehrlichiosis is caused by Ehr. canis and
occasionally Ehr. chaffeensis; canine granulocytic ehrlichiosis is
caused by Ana. phagocytophilum and Ehr. ewingii; equine granulocytic
ehrlichiosis is caused by Ana. phagocytophilum; equine monocytic
ehrlichiosis/Potomac horse fever is caused by N. risticii; tick-borne
fever is caused by Ana. phagocytophilum; Sennetsu fever is caused by N.
sennetsu; ehrlichiosis in cats is caused by Ana. phagocytophilum, and
ehrlichiosis in nonhuman primates is caused by Ehr. chaffeensis.
Zoonotic species include Ehr. chaffeensis, Ehr. ewingii, Ana.
phagocytophilum, and N. sennetsu (Ehr. canis has been zoonotic, but this
is not confirmed). The bacteria in this group of organisms are small,
pleomorphic, nonmotile, gram-negative, obligate, intracellular bacilli
(they parasitize leukocytes). These bacteria survive only briefly
outside the host (reservoir or vector) and only multiply
intracellularly. Ehr. chaffeensis, Ehr. canis, and Ana. phagocytophilum
have worldwide distribution. Ehr. ewingii has only been found in the
southeastern and southcentral United States. N. sennetsu has been
reported mainly in Japan, but is probably found in other parts of Asia
as well. Laboratory tests for ehrlichiosis or anaplasmosis in animals
and people include serology or detection of the organism. Bacterial
culture is not used because these organisms can be difficult to culture
and can take up to 30 days to grow. Detection of the organism is done by
finding morulae in peripheral blood smears or impression smears from
fresh tissues stained with Giemsa or by immunofluorescence. Serologic
tests in animals include indirect immunofluroescent antibody tests
(equine granulocytic ehrlichiosis, canine ehrlichiosis/anaplasmosis, and
tick-borne fever), ELISA tests (canine monocytic ehrlichiosis and canine
granulocytic anaplasmosis), immunoblotting techniques such as Western
blotting (research use). PCR assays that detect antigens in blood are
available for some types of ehrlichiosis. Human monocytic ehrlichiosis
and human granulocytic anaplasmosis are diagnosed by a fourfold rise or
fall in antibody titer via immunofluorescence assay.
Ehrlichiosis/anaplasmosis are treated with tetracycline antibiotics in
both animals and people. The best way to prevent contracting
ehrlichiosis/anaplasmosis is to limit tick exposure.

Ticks that are removed from animals
people should be kept frozen in a plastic
bag for identification in case of illness.

Q FEVER

Overview

Q fever, also known as query fever, was first described in 1935 in
Australia by Dr. Edward Derrick who was investigating abattoir fever in
a group of 800 Brisbane slaughterhouse workers who had symptoms of
fever, headache, shivers, and sweats. He called the disease query fever
because its causative agent was unknown. In 1936, Drs. Burnet and
Freeman successfully identified rickettsial bacteria as the infectious
agent of Q fever based on agglutination of infected animal tissues with
convalescent sera obtained from Q fever patients. Dr. Derrick named the
organism Rickettsia burnetti in honor of Dr. Burnet. In the United
States around the same time period, scientists at the Rocky Mountain
Laboratory in Montana were conducting research on the Nine Mile agent, a
microbe transmitted by ticks. Dr. Herald Rae Cox is credited with
identifying the "nine mile agent" as a rickettsial bacterium.
In the United States, Dr. Cox called the organism Ri. diaporica in
recognition of its ability to pass through filters used in those times
to distinguish between bacteria (impermeable) and viruses (permeable).
The bacterium has since been reclassified placing it genus on its own
called Coxiella, within the family of Legionellaceae. The
bacterium's name, Coxiella burnetii, honors the contributions of
both Dr. Burnet and Dr. Cox.

Q fever has been known as abattoir fever (because of the epidemic
among

slaughterhouse workers), Balkan grippe (because of the epidemic
among soldiers in the Balkans), and goat boat fever (because the disease
commonly occurred among boat crews transporting infected goats). Allied
forces experienced Q fever outbreaks in Italy and other Mediterranean
countries during World War II.

Explosive outbreaks of Q fever occurred in slaughterhouses in Texas
and Chicago in the 1940s and the disease is still recognized as an
occupational hazard among slaughterhouse workers.

Causative Agent

Cox. burnetii can survive for months and
even years in dust or soil.

Cox. burnetii is a small, aerobic, gram-negative coccobacillus that
is an obligate intracellular parasite in eukaryotic cells; however,
unlike other rickettsial bacteria it multiplies in the acidic
environment of phagosomes. Cox. burnetii forms an internal, stable,
resistant infective body (sometimes called a spore) that is similar in
structure and function to an endospore of some gram-positive bacilli.
This infective body allows the bacterium to survive harsh environmental
conditions. Cox. burnetii exists in two antigenic states: phase I (the
virulent form which is also known as the smooth phase) and phase II (the
avirulent form which is also known as the rough phase). The different
states relate to its cell coating (changes in lipopolysaccharides) and
antigenic, pathogenic, and immunogenic properties. Phase I bacteria
possess a full complement of lipopolysaccharides, whereas phase II
bacteria posses a simpler structure. The phase I bacterium is the form
isolated from animals and is highly infectious; the phase II bacterium
is isolated in cultured cell lines and is not infectious.

Epizootiology and Public Health Significance

Cox. burnetii does not replicate in
bacteriologic culture media.

Cox. burnetii is distributed worldwide except in New Zealand. It
has been found in various wild and domestic mammals, arthropods, and
birds. Domestic cattle, sheep, goats, dogs, and cats are susceptible to
infection, and the disease is found in most areas where these animals
are kept. Both Ixodidae (hard) and Argasidae (soft) ticks can be
reservoirs of the organism with greater than 40 species of ticks serving
as natural reservoirs that remain infected throughout life and can
transmit the bacterium transovarially. Infected animals shed this
bacterium in urine, feces, reproductive tissues/fluid, and milk.

In 1999, Q fever became a notifiable disease in many U.S. states
but reporting is not required in many other countries. In the United
States Q fever is a reportable disease in all states except Delaware,
Iowa, Oklahoma, Vermont, and West Virginia. In 2001, 26 cases of Q fever
were reported to the CDC and in 2002, 61 cases of Q fever were reported
to the CDC (0.05 per 100,000 people). The incidence of Q fever worldwide
varies in frequency and presentation from country to country.

The mortality rate with acute Q fever is reportedly as high as
2.4%. People at greatest risk for infection are veterinarians, farmers,
sheep and dairy workers, and laboratory workers who work with this
organism.

Transmission

Cox. burnetii is transmitted via inhalation, direct or indirect
contact with infected animals, or direct or indirect contact with their
dried excretions. People typically contract Q fever by inhaling
contaminated droplets of the highly infectious phase I spore forms
excreted by infected animals. Consumption of raw milk has also been
associated with infection. Infected ruminants can shed Cox. burnetii in
their milk and amniotic fluid, and animals or humans can be infected by
inhaling aerosols from the amniotic fluid or from unpasteurized infected
milk. Pregnancy stimulates the replication of bacteria in reproductive
and mammary gland tissues of many mammals. The amniotic fluid of
infected animals carries high numbers of bacteria and is particularly
dangerous. Person-to-person transmission is extremely rare. As a result
of its inhalational route of transmission, it can be used as a
biological agent and is classified as a category B agent.

The most important transmission route
from domestic ruminants to humans
is through airborne transmission of
particles from reproductive fluids.

Transmission occurs among wild and domestic animals by the bites of
ticks (humans are not typically infected by tick bites, although it may
be possible). Animal-to-animal transmission can also be through airborne
particles or direct contact and ingestion of reproductive tissues/fluids
or milk.

Pathogenesis

Once inside the body, Cox. burnetii is phagocytized by host cells
and replicates within vacuoles. The incubation period varies from 9 to
40 days (average 18 to 21 days) during which time bacteria proliferate
in the lungs, are engulfed by macrophages, and are transported to the
lymph nodes. From the lymph nodes bacteria are carried to the
bloodstream where they reach many areas of the body.

As few as ten Cox. burnetii can initiate
infection.

Clinical Signs in Animals

Goats, sheep, and cattle are the primary domestic reservoirs of
Cox. burnetii (Figure 4-22). Inapparent infection is typical in these
animals since clinical signs of infection rarely develop in infected
livestock. If the infected animal is pregnant, abortion sometimes
results. Occasionally an abortion storm (series of abortions) occurs
when Q fever passes through a previously uninfected flock or herd. If a
flock or herd is infected, most animals in the group will be infected.

[FIGURE 4-22 OMITTED]

Clinical Signs in Humans

In people, Q fever can present as an inapparent, acute, or chronic
disease.

* Inapparent Q fever is seen in about half of the people infected
with Cox. burnetii and these people do not show any clinical signs.

* Acute Q fever is a generalized disease that presents like
influenza. The incubation period is 2 to 4 weeks (average is 20 days).
Clinical signs include sudden fever, chills, lethargy, muscle and joint
pain, headache, and photophobia. This flu-like syndrome is usually
self-limiting and lasts up to three weeks. Pneumonia can occur in about
one third of people. Hepatitis can also occur alone or concurrently with
pneumonia. Less common features of acute Q fever include rashes,
meningitis, myocarditis, and pericarditis.

* Chronic Q fever develops in individuals who have been infected
for over 6 months without effective treatment. Its main feature is
endocarditis and/or chronic hepatitis. Clinical signs include prolonged
fever, night sweats, chills, fatigue, and shortness of breath.

Diagnosis in Animals

Necropsy lesions in animals with Q fever are nonspecific and of
little value in diagnosing the disease. Cox. burnetii cannot be cultured
using current bacteriologic media. Serologic testing is the diagnostic
tool of choice with complement fixation, IFA, and ELISA tests available.

Diagnosis in Humans

In people, Q fever is confirmed by serology using IFA (most widely
used). Immunohistochemical staining methods and PCR tests are also
available. Because Cox. burnetii exists in two antigenic phases,
assessing both phase I and phase II levels are important in diagnosis;
therefore, baseline and 3- to 4-week samples are taken for analysis. In
acute Q fever, the antibody level to phase II is usually higher than
phase I and is generally first detectable during the second week of
illness. A fourfold rise in complement-fixing antibodies against phase
II antigen confirms acute Q fever. In acute Q fever, patients will have
IgG antibodies to phase II and IgM antibodies to phases I and II. In
chronic Q fever, high levels of antibody to phase I in combination with
constant or falling levels of phase II antibodies are found. Antibodies
to both phase I and II antigens have been shown to last for months or
years after initial infection. Increased IgG and IgA antibodies to phase
I are often indicative of chronic Q fever.

Treatment in Animals

In animals, tetracycline antibiotic treatment is effective for
treating Q fever. Separation of pregnant animals and burning or burying
infective reproductive tissues/ fluids can reduce the spread of
bacteria. Resistance to physical and chemical agents makes ridding the
environment of Cox. burnetii difficult. Recommended disinfectants
include a formulation of two quaternary ammonium compounds, 70% ethanol,
and 1:10 bleach solution.

Antibodies to phase I antigens generally
take longer to appear and indicate
continued exposure to Cox. burnetii.

Treatment in Humans

Antibiotics are used to treat both acute and chronic Q fever. The
most common treatment is doxycycline for acute Q fever and combinations
of doxycycline plus an additional antibiotic such as fluoroquinolone,
rifampin, or trimethoprimsulfamethoxazole for chronic Q fever. Chronic Q
fever antibiotic treatment is recommended for 3 years. Disinfection of
contaminated areas is also important.

Management and Control in Animals

There is not a vaccine to protect animals from acquiring Cox.
burnetii. Proper hygiene, especially around birthing animals, is
important in preventing animal-toanimal spread of disease.

Management and Control in Humans

A formalin inactivated phase I whole cell vaccine is licensed in
Australia and Eastern Europe (a single dose provides greater than 95%
protection against naturally occurring Q fever within 3 weeks and lasts
for at least 5 years). A live attenuated vaccine (Strain M44) has been
used in the former USSR. In the United States, a noncommercial
inactivated vaccine is available for at risk laboratory personnel
through the U.S. Army Medical Research Institute. Standard precautions
are recommended for health care workers taking care of patients with
suspicion or diagnosis of Q fever.

* Ensuring that sheep holding facilities are located away from
populated areas. Animals should be routinely tested for antibodies to
Cox. burnetii, and measures should be implemented to prevent airflow to
other occupied areas.

Q fever is an infection caused by the bacterium Cox. burnetii, a
small, aerobic, gram-negative coccobacillus that is an obligate
intracellular parasite in eukaryotic cells. Cox. burnetii forms an
internal, stable, resistant infective body that allows the bacterium to
survive harsh environmental conditions. Cox. burnetii exists in two
antigenic states: the highly infectious phase I (the virulent form which
is also known as the smooth phase) and the noninfectious phase II (the
avirulent form which is also known as the rough phase). Cox. burnetii
does not replicate in bacteriologic culture media.

Cattle, sheep, and goats are the primary reservoirs of Cox.
burnetii. Clinical disease is rare in these animals, although abortion
in pregnant ruminants may occur. Organisms are excreted in milk, urine,
and feces of infected animal; and high numbers of bacteria are shed in
amniotic fluids and the placenta. Infection of humans usually occurs by
inhalation of these organisms from air that contains airborne particles
contaminated by infected animals. Ingestion of contaminated milk is a
less common mode of transmission. In people Q fever can cause flu-like
signs, pneumona, and hepatitis in its early form, and endocarditis in
its chronic form. Q fever is diagnosed by serology and treated with
antibiotics such as doxycycline. In the United States, Q fever outbreaks
have resulted mainly from occupational exposure involving veterinarians,
slaughterhouse workers, sheep and dairy workers, livestock farmers, and
laboratory workers. Prevention and control efforts should be directed
primarily toward these groups and environments.

ROCKY MOUNTAIN SPOTTED FEVER

Overview

Rocky Mountain spotted fever (RMSF), originally known as black
measles because of its characteristic rash and referred to as tick
typhus outside the United States, is the most important rickettsiosis in
the western hemisphere. RMSF is one of the spotted fevers, a large group
of arthropod-borne infections caused by closely related Rickettsiae
bacteria. Rickettsiae are small, gram-negative, pleomorphic (cocci or
small bacilli) bacteria that are obligate intracellular parasites of
eukaryotic cells. Rickettsioses are rickettsial infections in which
mammals are the hosts and arthropods are the vectors.

RMSF was first recognized in 1896 in Idaho as a frequently fatal
disease affecting hundreds of people in the Snake River Valley area.
Outbreaks of RMSF spread rapidly and by the early 1900s, its geographic
distribution in the United States went as far north as Washington and
Montana and as far south as California, Arizona, and New Mexico. In
response to its rapid spread and severity of clinical signs, the Rocky
Mountain Laboratory was established in Hamilton, Montana (it is
currently part of the National Institute of Allergy and Infectious
Diseases, National Institutes of Health).

RMSF is caused by the bacterium Rickettsia rickettsii, named after
Dr. Howard T. Ricketts, the first person to identify the infectious
organism causing this disease in blood smears of infected animals and
humans. Ricketts and his researchers also identified the cycle of
infection involving ticks and mammals with humans considered accidental
hosts and not a critical component in the natural transmission cycle of
Ri. rickettsii. In 1910 after completing his work on RMSF, Ricketts died
of typhus, a different rickettsial disease.

In the 1930s, it became clear that RMSF occurred in many areas of
the United States other than the Rocky Mountain region. This vast
distribution is a result of the ticks that serve as vector and reservoir
of the disease: Dermacentor variabilis (commonly known as the American
dog tick) in the eastern United States and Dermacentor andersoni
(commonly known as the Rocky Mountain wood tick) in the western United
States. The majority of RMSF cases are currently concentrated in the
southeast and eastern seaboard regions of the United States as well as
southern Canada, Central America, Mexico, and parts of South America.

Causative Agent

RMSF is caused by Ri. rickettsii, a small bacterium in the family
Rickettsiaceae (which consists of genera: Rickettsia and Orientia).
Rickettsiae are fastidious, nonmotile, aerobic, gram-negative, obligate
intracellular bacteria that survive only briefly outside the host. They
only multiply intracellularly in the cytoplasm of host cells.
Rickettsiae have cell walls consisting of small amounts of peptidoglycan
(making them seem as though they lack a cell wall) and an outer
lipopolysaccharide membrane that has little endotoxin activity. The
bacterium is surrounded by a loosely organized slime layer causing them
not to react well to Gram stain; hence they stain a pale pink. This
slime layer is believed to play a role in transmission. Tick feeding
results in growth of the slime layer (called reactivation) and is
believed to attribute to the bacterium's virulence. To better
visualize these bacteria Giemsa stain is routinely used. Rickettsiae
consist of three groups of bacteria: the spotted fever group, the typhus
group, and the scrub typhus group. More than 20 species of Rickettsia
are known and not all of them cause disease.

Over 90% of RMSF infections occur
between April and September when
increased numbers of adult and
nymphal Dermacentor ticks are seen.
Infection can occur during winter in
warmer regions such as Central and
South America.

Epizootiology and Public Health Significance

The distribution of Rickettsiae is limited to the geographic region
of their arthropod hosts. RMSF was originally found in the western
United States; however, in the last 100 years there has been a shift to
the eastern United States with the occurrence of disease highest in the
south-Atlantic region (Delaware, Maryland, Washington D.C., Virginia,
West Virginia, North Carolina, South Carolina, Georgia, and Florida).
Infection also occurs in other parts of the United States, such as the
Pacific region (Washington, Oregon, and California) and west
south-central region (Arkansas, Louisiana, Oklahoma, and Texas). The
states with the highest incidences of RMSF are North Carolina and
Oklahoma.

RMSF has been a reportable disease in the United States since the
1920s. Approximately 600 to 800 cases of RMSF are reported annually in
the United States, although many cases go unreported. RMSF is highest
among males, Caucasians, and children with two-thirds of the cases
occurring in children younger than 15 years of age (peak age being 5 to
9 years old). People with frequent exposure to dogs and who reside near
wooded areas or areas with high grass are at increased risk of
infection. Seasonal outbreaks parallel tick activity with 90% of cases
reported from April 1 to September 30 (peaks seen in May and June).
Human RMSF mortality rates are approximately 4%, with death usually
occurring 8 days after onset of symptoms.

Transmission

In general, about 1% to 3% of the tick
population carries Ri. rickettsii making
the risk of exposure low even in areas
where the majority of human cases are
reported.

Ri. rickettsii bacteria typically infect and are transmitted by
Ixodidae (hard) ticks. Ri. rickettsii is most frequently transmitted to
a vertebrate host through saliva while the tick feeds. It usually takes
several hours (between 6 and 10) of attachment and feeding before Ri.
rickettsii is transmitted to the host. After an immature tick develops
into the next stage, Ri. rickettsii may be transmitted to a second host
during the feeding process. This bacterium may also be transmitted to a
vertebrae host through contact with infected tick hemolymph or excrement
when engorged ticks are crushed.

There are two major Ixodidae tick vectors of Ri. rickettsii in the
United States: Dermacentor variabilis and De. andersoni. De. variabilis
is found east of the Rocky Mountains and in limited areas on the Pacific
Coast (Figure 4-23 and Figure 4-2). Dogs and medium-sized mammals are
the preferred hosts of adult De. variabilis ticks. De. variabilis also
feeds on other large mammals (including humans) and is the tick most
commonly responsible for transmitting Ri. rickettsii to humans. De.
andersoni is found in the Rocky Mountain states and in southwestern
Canada. Adult ticks feed primarily on large animals, whereas larvae and
nymphs feed on small rodents. The life cycle of this tick may require up
to 2 to 3 years for completion.

[FIGURE 4-23 OMITTED]

The ticks Rhipicephalus sanguineus (in Mexico) (Figure 4-1) and
Amblyomma cajennense (in Central and South America) have been shown to
be naturally and experimentally infected with Ri. rickettsii. Although
these species play only a minor role in the transmission of Ri.
rickettsii in the United States, they are important vectors of RMSF in
Central and South America.

Ticks become infected with Ri. rickettsii by two methods. One way
ticks acquire the bacterium is by feeding on infective small mammals
reservoirs such as chipmunks and squirrels. Dogs and humans may also
serve as reservoirs for RMSF; however, they are incidental hosts and are
the only reservoirs that show clinical signs. The larva and nymph forms
of Dermacentor ticks feed on small mammals, whereas the adult ticks feed
on larger mammalian hosts. Larger mammals rarely achieve the level of
organisms in blood necessary to transmit disease to a feeding tick;
therefore, it is the larva and nymph stages that are frequently infected
with Ri. rickettsii during feeding on small mammals.

The second way ticks can become infected with Ri. rickettsii is via
other ticks. Transstadial spread of RMSF occurs through the transfer of
bodily fluids or spermatozoa during mating from one tick to another.
Transovarial spread of RMSF occurs from the pregnant female tick to her
eggs. Transovarial infection is the primary means by which Ri.
rickettsii is spread in nature.

Pathogenesis

Ri. rickettsii enter the skin typically through a tick bite and
undergoes a 3- to 14-day (usually 7 day) incubation period in which the
organism replicates. Following the incubation period, bacteria spread
via lymphatics to the bloodstream and attach to endothelial cells of
venules and capillaries and begin replicating. This bacterial
replication causes vasculitis and increased vascular permeability. Fluid
moves to the interstitial spaces leading to edema (typically in the
extremities including the scrotum, prepuce, and ears), hemorrhage,
hypovolemia, shock, and vascular collapse. Severity of the vasculitis
can be directly correlated to the infective dose. Vascular endothelial
damage contributes to development of petechiae and ecchymotic
hemorrhages as a result of the destruction of platelets in response to
vasculitis. Petechial hemorrhages are often seen on exposed mucosal
surfaces in the dog. Organ damage, secondary to vascular collapse, is
common in the brain, skin, heart, and kidneys. Vascular leakage also
triggers activation of the animal's platelets and coagulation
system. In skin, vascular injury initially appears as erythematous (red)
macules that are usually 1 to 5 mm in diameter and progress to the
classic petechial rash of RMSF. Because of damage to the vascular system
RMSF is a multisystem disease.

Once infected, a tick can carry
Ri. rickettsii for life.

Clinical Signs in Animals

Ri. rickettsii causes disease in dogs. RMSF, also known as tick
fever in dogs, is usually seen in dogs younger than 3 years old with a
recent history of exposure to ticks or their habitat. RMSF is usually
reported in dogs between the months of March and October when there is
an increased prevalence of ticks in the environment. Early signs may
include fever (up to 105[degrees]F), anorexia, lymphadenopathy,
polyarthritis, coughing or dyspnea, abdominal pain, and edema of the
face or extremities. In severe cases petechial hemorrhages may be seen
on the mucous membranes. Neurologic signs, such as altered mental
states, vestibular dysfunction, and hyperesthesia, are commonly seen
with RMSF. Focal retinal hemorrhage is usually seen in the early stages
of this disease.

Dogs are susceptible to RMSF and serve
as excellent sentinels of the disease.

Clinical Signs in Humans

RMSF in humans typically presents with three classic signs: fever,
rash, and history of tick bite. Initial clincial signs may include
fever, nausea, vomiting, severe headache, muscle pain, and lack of
appetite. The rash appears 2 to 5 days after the onset of fever and is
often very subtle appearing as small, flat, pink, nonitchy macules
(spots) on the wrists, forearms, and ankles (Figure 4-24). These macules
turn pale when pressure is applied and eventually become raised on the
skin. Younger people usually develop the rash earlier than older people.
Clinical signs that appear later in the disease include rash, abdominal
pain, joint pain, and diarrhea. The classic red, petechial rash of RMSF
is usually not seen until the sixth day or later after disease onset and
occurs in only 40% to 60% of patients. The rash usually involves the
palms or soles.

[FIGURE 4-24 OMITTED]

Diagnosis in Animals

Laboratory abnormalities seen in dogs with RMSF include
thrombocytopenia (platelet counts ranging from 23,000 to
220,000/[micro]l); a moderate leukocytosis with a mild left shift (a
mild leucopenia occurs early in infection); normocytic, normochromic
anemia; azotemia, elevated glucose, cholesterol, alkaline phosphatase
(ALP) and alanine aminotransferase (ALT); and hyponatremia,
hypocalcemia, and hypoalbuminemia (secondary to vasculitis). Definitive
diagnosis of RMSF is through IFA serologic testing along with clinical
signs. IFA can be used to detect either IgG or IgM antibodies. Blood
samples taken early (known as the acute sample) and late (known as the
convalescent sample) in the disease are the preferred specimens for
evaluation. IgG antibody titers to Ri. rickettsii that increase or
decrease fourfold are considered diagnostic for RMSF but may not be
clinically useful because IgG antibody concentration does not increase
until 2 to 3 weeks postinfection. A single high IgG titer (> 1024) is
suggestive of exposure within the last tick season, whereas a single
positive IgM titer (> 8) indicates a more recent exposure. Positive
IgG titers may persist for 3 to 10 months following infection; however,
positive IgM titers normally decrease after 4 weeks. Cross-reactivity to
other spotted fever Rickettsiae exist and may affect test
interpretation.

Diagnosis in Humans

Laboratory abnormalities suggestive of RMSF in humans may include
abnormal white blood cell counts, thrombocytopenia, hyponatremia, or
elevated liver enzyme levels. Serologic assays are most frequently used
for confirming cases of RMSF, which include IFA, ELISA, latex
agglutination, and immunoassays. In humans increased IgM titers appear
by the end of the first week of illness and diagnostic levels of IgG
antibody do not appear until 7 to 10 days after the onset of illness.
The most rapid and specific diagnostic assays are PCR tests, which can
detect DNA present in as few as 5 to 10 bacteria in a sample. PCR
testing is done on fresh skin biopsies or fixed or unfixed tissues
samples. Diagnosis can be confirmed by isolation of Ri. rickettsii from
clinical samples such as whole blood and biopsies. Isolation may require
several weeks and samples should be shipped unfrozen or frozen and on
dry ice to the CDC. Immunostaining is another method used to identify
Ri. rickettsii from a skin biopsy of the rash from an infected person
prior to therapy, but may not always detect the bacterium as a result of
its focally distributed lesions.

Treatment in Animals

In dogs, antibiotic treatment is initiated immediately after
samples are taken for laboratory testing to reduce the disease signs.
Tetracycle or doxycycline is the treatment of choice with
chloramphenicol recommended in pregnant bitches and puppies younger than
6 months of age to avoid dental staining in growing fetuses/ puppies.
Supportive care should be considered along with antibiotic
administration; however, fluid therapy should be administered
conservatively as a result of the vasculitis and potential for pulmonary
and cerebral edema. Mild ocular lesions should resolve with systemic
antibiotic therapy and the use of topical corticosteroids may help
conditions such as uveitis. Dogs that have recovered from RMSF have
protective immunity to further reinfection.

Treatment in Humans

Treatment of RMSF in humans involves the use of antibiotics such as
doxycycline for at least 3 days after fever subsides. Tetracycline and
chloramphenicol are alternative antibiotics used to treat RMSF; however,
they are associated with side effects that limit their use.

Management and Control in Animals

The best way to prevent dogs from contracting RMSF is to limit
their tick exposure particularly between the months of March through
October. Dogs should be inspected daily for ticks and any ticks that are
found should be removed quickly and safely with a gloved hand. Topical
agents (such as fiprinol or permethrin) and tick collars containing
amitraz are effective methods of tick control. There is not a vaccine
for protection against Ri. rickettsii.

Management and Control in Humans

The best way to prevent RMSF in people also includes tick control.
Strategies to reduce ticks include area-wide application of acaricides
(chemicals that will kill ticks and mites), application of tick
repellent with DEET, and control of tick habitats. Prompt removal of
ticks is also essential. Tick control has been covered in a previous
section and should be referred to.

Summary

RMSF is a clinical disease of humans and dogs (with small mammals
occasionally infected) that is caused by Ri. rickettsii. Ri. rickettsii
is a small, gram-negative bacterium that is spread to humans and dogs by
the Ixodidae ticks De. andersoni and De. variabilis. Clinical signs in
dogs include fever, anorexia, lymphadenopathy, polyarthritis, coughing
or dyspnea, abdominal pain, edema of the face or extremities, petechial
hemorrhages, neurologic signs, and retinal hemorrhage. Clinical signs in
people include fever, headache, and muscle pain, followed by development
of rash. The disease can be difficult to diagnose in the early stages,
and without prompt and appropriate treatment it can be fatal. RMSF is a
seasonal disease and occurs throughout the United States during the
months of April through September (peak tick times are March to
October). Most of the cases occur in the south-Atlantic region of the
United States (Delaware, Maryland, Washington D.C., Virginia, West
Virginia, North Carolina, South Carolina, Georgia, and Florida) and the
highest incidence rates have been found in North Carolina and Oklahoma.
RMSF is diagnosed based on clinical signs and serologic testing such as
IFA. Treatment involves the use of antibiotics such as doxycycline. Once
a person or dog clears the infection it is believed that they have long
lasting immunity to Ri. rickettsii. The disease is prevented by
controlling ticks.

Review Questions

Multiple Choice

1. The tick-borne disease that manifests initially as erythema
migrans and later as chronic arthritis is

a. Rocky Mountain spotted fever.

b. Lyme disease.

c. relapsing fever.

d. ehrlichiosis.

2. What is not a characteristic of the Rickettsiae

a. obligate intracellular organisms.

b. transmitted by arthropods.

c. gram-negative, pleomorphic bacilli.

d. multiply extracellularly.

3. What disease can be transmitted by aerosol inhalation?

a. Q fever

b. tularemia

c. Rocky Mountain spotted fever

d. Lyme disease

4. A 19-year-old female is admitted to a local hospital with fever,
chills, headache, and a rash on her palms and soles. The woman states
that she has recently been bitten by a tick. The physician has ruled out
babesiosis and Lyme disease based on laboratory tests. The probable
cause of her symptoms is infection with

a. Coxiella burnetii.

b. Rickettsia rickettsii.

c. Ehrlichia canis.

d. Borrelia burgdorferi.

5. What is false regarding ticks?

a. They have long life cycles.

b. They consume large volumes of blood.

c. They produce large numbers of eggs.

d. They have three body regions: capitulum, idiosoma, and scutum.

6. All ticks undergo which basic stages?

a. egg, larva, nymph, adult

b. egg, nymph, adult

c. egg, larva, adult

d. egg, larva, nymph, instar

7. The process by which ticks crawl up a piece of grass or perch on
leaf edges with their front legs extended is called

a. perching.

b. questing.

c. trolling.

d. engorging.

8. Transfer of an infectious agent from one tick life stage through
molting to the next stage is called

a. horizontal transmission.

b. vertical transmission.

c. transovarial transmission.

d. transstadial transmission.

9. A common target in most rickettsioses is the

a. liver.

b. nervous system.

c. endothelial lining of small blood vessels.

d. lymphatic channels.

10. Bacteria that cause ehrlichiosis bind to and are named for the
type of cell they infect. These cells are

21. A 41-year-old man was admitted to the hospital complaining of
severe headache, moderate fever, chest pain, and a productive cough.
Swollen lymph nodes and a tender, enlarged liver were noted on the
examination. This man is a professional furrier and trapper and had
recently returned from an excursion on which he had trapped and skinned
approximately 50 rabbits. Routine sputum and blood cultures were
collected and revealed very faintly staining gram-negative bacilli on
Gram stain and no growth on routine bacteriological media (blood agar
and MacConkey) after 72 hours. After 6 days, growth was observed on
chocolate agar plates.

a. Given this person's history and symptoms, what disease
might he have?

b. What organism causes this disease?

c. Why did the organism grow on chocolate agar (what chemical does
this organism need for growth)?

d. What special precautions need to be taken when handling this
organism?

22. Almost 2 weeks after returning from a camping trip in the Grand
Canyon, a 50-year-old man developed fever, chills, headache, muscle
pain, and profuse sweating. These symptoms typically lasted for 2 days.
Over the next 2 weeks he experienced three febrile relapses and was
hospitalized. Physical examination and laboratory tests did not
conclusively lead to a diagnosis. While in the hospital the patient had
a fourth episode of fever during which time a peripheral blood sample
was taken and examined. Spirochetes were observed and although the
patient did not remember a tick bite, he was treated with tetracycline
and recovered.

a. What disease did this patient most likely have?

b. What is the causative agent of this disease?

c. What is the vector of endemic relapsing fever?

d. What is the vector of epidemic relapsing fever?

23. A 3-year-old male Coonhound presented to the clinic with an
acute fever (T=104[degrees]F), anorexia, and lameness. Physical
examination reveals a swollen left rear hock.

a. What questions would you want to ask this owner when taking the
animal's history?

b. What test would you recommend for this dog?

c. If this test comes back positive, what would be used to treat
this dog?

d. What preventative measures could this owner take to prevent this
disease?

Levy, S. 2002. Use of a C6 ELISA test to evaluate the efficacy of a
whole-cell bacterin for the prevention of naturally transmitted canine
Borrelia burgdorferi infection. Veterinary Therapeutics 3(4):420-4.

Levy, S., K. Clark, and L. Glickman. 2005. Infection rates in dogs
vaccinated and not vaccinated with an OspA Borrelia burgdorferi vaccine
in a Lyme disease-endemic area of Connecticut. International Journal
Applied Research Veterinary Medicine 3(1):1-5.